S-ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide-Induced Depression Via Targeting SIRT2.
Advanced science (Weinheim, Baden-Wurttemberg, Germany) April 2, 2025 Cong Lin, Xiaoxuan Zhou, Mingqi Li et al. 14 citations
In a mouse model of inflammation-induced depression, S-ketamine (S-KET) reduced depressive-like behaviors and lowered pro-inflammatory factors in the medial prefrontal cortex, while R-ketamine (R-KET) did not. S-KET bound directly to the protein SIRT2 at the Q167 residue, enhancing its interaction with NF-κB subunit p65, which reduced acetylation and suppressed pro-inflammatory gene expression. Experiments using RNA interference, a SIRT2 inhibitor (AK-7), and pharmacological blockade confirmed that SIRT2 is essential for these effects. The findings indicate that SIRT2 mediates the therapeutic actions of S-KET, suggesting a target for treating inflammation-associated depression.